Program: Oral and Poster Abstracts
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II
Aims
In relapsed/refractory MM (R/R MM) patients refractory to prior LEN: To determine the maximum tolerated dose (MTD) of oral AZA when administered in combination with fixed dose LEN and dexamethasone (DEX); to characterise safety and tolerability; to assess efficacy: overall response rate (ORR), progression free survival (PFS), overall survival (OS).
Methods
Phase Ib, single centre, 3 x 3 paradigm dose escalation study with expansion at MTD. LEN 25mg/d for d1-21/28d cycle and DEX 40mg d1, 8, 15, 22/28 were combined with escalating doses of AZA: initial dose was 100mg for d1-14/28, increasing by either 7 days or 50mg per cohort, to a maximum of 200mg d1-21/28d. Dose limiting toxicity (DLT) was assessed during cycle 1. IMWG uniform response criteria and modified EBMT criteria (minor response, MR) were used. Treatment continued until toxicity/progression. Following review by the independent monitoring committee, an expansion of cohort 2 (100mg d1-21) was undertaken due to the efficacy signal seen in this cohort. This is an interim report.
Results
18 eligible MM patients commenced therapy (7 F, 11 M) at a median age of 64 years (range 50-80 years). Median number of prior lines of therapy was 5 (range 2-8), including 15 patients with prior ASCT (8 with 2 prior ASCT) and 2 patients with prior Allogeneic transplant. All had previously failed LEN (R/R = 15, primary refractory (PrimR) = 3); eight also received pomalidomide (POM) (R/R = 3, PrimR = 5). All had been treated with bortezomib (BTZ) (R/R = 8, PrimR = 8). 16 patients were both BTZ and LEN refractory.
MTD Determination: AZA dose achieved at the time of submission was 150mg d1-21, with no DLTs observed. One patient was not evaluable as they progressed prior to completion of the first cycle.
Safety/tolerability: All grade haematologic toxicity comprised anaemia 5/18 (grade (G) 3/4: 3), neutropenia 6/18 (G 3/4: 5) and thrombocytopenia 9/18 (G 3/4: 3). All non-haem toxicity (>11%) consisted of: nausea 14/18 (G 3/4: 1), vomiting 6/18, constipation 7/18 (G 3/4: 1), fatigue (10, G 3/4: 2), insomnia 3, infection URTI 6/18, LRTI 2, (G 3/4: 2). All but 1 patient required antiemetic therapy to tolerate AZA. Two patients required dose reductions of AZA, two for LEN and three for DEX.
Efficacy: ORR (≥PR) was 39% (7/18): 6 PR, and 1 VGPR. Of the remaining patients, 2 achieved MR, 6 SD, and 3 PD, giving an overall clinical benefit rate (CBR) of 50%. Responses were seen in all but one cohort [100mg d1-14 (3 PR), 100mg d1-21 (1 VGPR, 1 PR), 150mg d1-14 (nil), and 150mg d1-21 (2 PR, 2 MR)]. Time to achieve best response in patients with ≥ MR was 2.7m (1-3.7m). Two of five patients treated with LEN in prior 1-2 treatment lines responded (PR, VGPR), one had SD (duration of response (DoR): 5m). One of eight patients treated with POM in prior 1-2 treatment lines responded (PR), with 2 achieving MR and 3 SD (DoR: 2, 3 and 6m). Median PFS 3.8m, median OS 14.5m. Median time on study was 3.7m (0.3-12.9m). Four patients remain on study.
Conclusion
Oral AZA in combination with LEN and DEX appears to be well tolerated and effective in a group of heavily pre-treated R/R MM patients, including within a subgroup of patients who have recently failed IMiD therapy, suggesting that AZA may overcome drug resistance in R/R MM. The MTD has not yet been determined.
Disclosures: Off Label Use: oral azacitidine in patients with relapsed/refractory myeloma.
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